Systematic analysis of telomere length and somatic alterations in 31 cancer types

Abstract

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Tumor telomeres were shorter compared to normal tissues, and longer in sarcomas and gliomas compared to other cancers. Amongst 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, and predicted telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, mostly with undetectable TERT, harbored ATRX or DAXX alterations, demonstrated elongated telomeres and increased telomeric repeat containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT, nor harbored alterations in ATRX/DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

“…2C,D, S3C). Note that these results are opposite to the expectation from the literature of increased TERT gene expression correlating with high CpG methylation in other cell types (Barthel et al, 2017; Guilleret and Benhattar, 2004), but are consistent with our data on the four related bladder cancer lines (Fig. 2A,B).…”

“…To explore this non-canonical relationship with 5mC in more detail, we chose to study cancers with heterozygous −124 mutations, capitalizing on the fact that these cells contain TERT alleles maintained in different transcriptional states. We reasoned that if TERT CGI methylation were a positive regulator of TERT mRNA expression in these cells as suggested by previous studies (e.g., Barthel et al, 2017), we should observe higher levels of 5mC on the active promoter-mutant allele.…”

“…Here, however, the TERT gene has been an outlier. TERT expression in most previously studied cancers is associated with increased 5mC in the TERT promoter CGI (Barthel et al, 2017; Dessain et al, 2000; Devereux et al, 1999) Thus, in these cancers, TERT transcription occurs despite this gain of 5mC. To explore this non-canonical relationship with 5mC in more detail, we chose to study cancers with heterozygous −124 mutations, capitalizing on the fact that these cells contain TERT alleles maintained in different transcriptional states.…”

Cancer Risks Linked to the Bad Luck Hypothesis and Epigenomic Mutational Signatures

“…However, the level of telomerase activity is low or absent in the majority of stem cells, even within tissues with a low cell turnover, such as those of the brain and bone [22]. Nonetheless, TERT DNA promoter methylation results in TERT expression [23]. Thus, telomerase activity and telomere maintenance can lead to the immortalization of germline cells, embryonic stem cells, and cancer initiating cells [24].…”

TERTgene: its function and dysregulation in cancer

“…TERT has been shown to be amplified in approximately 4% of cancers, especially ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, oesophageal carcinoma and adrenocortical carcinoma 22. Rearrangements of the TERT promoter have been demonstrated in high-risk neuroblastomas 22 23.…”